title: Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.
abstract: BACKGROUND
  Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease.
  
  
  METHODS
  TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression.
  
  
  RESULTS
  TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis.
  
  
  CONCLUSIONS
  TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Mary-Clare
authors.initials: MC
authors.lastname: Cathcart
authors.forename: Kathy
authors.initials: K
authors.lastname: Gately
authors.forename: Robert
authors.initials: R
authors.lastname: Cummins
authors.forename: Elaine
authors.initials: E
authors.lastname: Kay
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: Graham P
authors.initials: GP
authors.lastname: Pidgeon
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D004791:Enzyme Inhibitors; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; D013930:Thromboxane-A Synthase